Method and composition for potentiating an opiate analgesic

ABSTRACT

Composition and methods of treating pain and reducing or reversing tolerance to opiate analgesics are disclosed. The composition and method utilize an opiate analgesic and an endothelin antagonist as active agents to treat pain in mammals, including humans.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 10/301,449,filed Nov. 21, 2002, pending, which claims the benefit of provisionalapplication Ser. No. 60/333,599, filed Nov. 27, 2001, each incorporatedhere by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to the treatment of pain using an opiateanalgesic and an endothelin receptor antagonist. More particularly, thepresent invention relates to a method of potentiating the effects of anopiate analgesic, like morphine, in a mammal by administration of atherapeutically effective amount of an endothelin receptor antagonist.The composition and method permit a reduction in the opiate analgesicdose to provide a desired analgesic effect, without effecting thecataleptic action of the opiate analgesic. The present invention alsorelates to a method of reducing or reversing tolerance to an opiateanalgesic in an individual undergoing opiate analgesic treatment byadministering a therapeutically effective amount of an endothelinreceptor antagonist. The present composition and methods also reduce theincidence of opiate analgesic addiction.

BACKGROUND OF THE INVENTION

Analgesics are agents that relieve pain by acting centrally to elevatepain threshold, preferably without disturbing consciousness or alteringother sensory functions. A mechanism by which analgesic drugs obtundpain (i.e., raise the pain threshold) has been formulated. Research inthis area has resulted in the development of a number of opiate andopioid analgesics having diverse pharmacological actions.

The available opiate and opioid analgesics are derivatives of fivechemical groups (i.e., phenanthrenes, phenylheptylamines,phenylpiperidines, morphinans, and benzomorphans). Pharmacologically,these opiates and nonopiates differ significantly in activity. Some arestrong agonists (morphine), others are moderates-to-mild agonists(codeine). In contrast, some opiate derivatives exhibit mixedagonist-antagonist activity (nalbuphine), whereas others are opiateantagonists (naloxone). Morphine is the prototype of the opiate andopioid analgesics, all of which have similar actions on the centralnervous system.

Morphine is an alkaloid chemically derived from opium papaversomniferum. Other drugs, such as heroin, are processed from morphine orcodeine. Such opiates have been used both medically and non-medicallyfor centuries. By the early 19th century, morphine had been extracted ina pure form suitable for solution. With the introduction of thehypodermic needle, injection of a morphine solution became the commonmethod of administration. Of the twenty alkaloids contained in opium,only codeine and morphine are still in widespread clinical use.

The opiates are among the most powerfully acting and clinically usefuldrugs producing depression of the central nervous system. Drugs of thisgroup are used principally as analgesics, but possess numerous otheruseful properties. Morphine, for example, is used to relieve pain,induce sleep in the presence of pain, check diarrhea, suppress cough,ease dyspnea, and facilitate anesthesia.

However, morphine also depresses respiration; increases the activity andtone of the smooth muscles of the gastrointestinal, biliary, and urinarytracts causing constipation, gallbladder spasm, and urinary retention;causes nausea and vomiting in some individuals; and can induce cutaneouspruritus. In addition, morphine and related compounds have otherproperties that tend to limit their usefulness.

For example, when morphine and related compounds are administered over along time period, tolerance to the analgesic effect develops, and thedose then must be increased periodically to obtain equivalent painrelief. Eventually, tolerance and physical dependence develop, which,combined with euphoria, result in excessive use and addiction of thosepatients having susceptible personalities. For these reasons, morphineand its derivatives must be used only as directed by a physician (i.e.,not in greater dose, more often, or longer than prescribed), and shouldnot be used to treat pain when a different analgesic will suffice.

Nevertheless, morphine remains the major drug for the treatment ofmoderate to severe pain (Foley, 1993). Opioids particularly are used totreat conditions lacking a standard treatment, such as cancer pain,trauma, myocardial infarction, post-operative pain, and neuropathicpain. However, opioid painkillers have significant adverse side effectslike respiratory depression, nausea, vomiting, dizziness, sedation,mental clouding, constipation, urinary retention, and severe itching.

These adverse side effects limit the usefulness of opioids, likemorphins, as painkillers. Therefore, several companies are developing anew generation of opioid painkillers, but advances in neuroscience havenot progressed a sufficient extent to provide a significantbreakthrough. Typically, companies are using proprietary technology toreformulate opioid drugs, such as morphine, into branded painkillerswith improved clinical benefits. To date, innovations in the field ofopioid painkillers have largely focused on increasing the convenience ofopioid drugs. For example, important advances have been made in opioiddelivery, such as sustained release formulations and transmucosaldelivery.

The present invention is directed to the discovery that somepharmacological actions of morphine can be modified by coadministrationof an endothelin receptor antagonist, hereafter termed an “endothelinantagonist.” U.S. patent publication US 2002/0082285 A1 discloses theuse of an endothelin antagonist in the treatment of pain.

SUMMARY OF THE INVENTION

The present invention is directed to administration of an endothelinantagonist in combination with an opiate analgesic. More particularly,administration of an opiate analgesic in combination with an endothelinantagonist potentiates the analgesic effect of opioids, and, therefore,lowers the dose of analgesic required to provide a desired pain-reducingeffect, without affecting the cataleptic properties of the analgesic.The reduced amount of opiate analgesic required to provide a desiredeffect reduces the severity of various adverse side effects associatedwith opiate analgesic treatment.

Accordingly, one aspect of the present invention is to provide acomposition comprising an opiate analgesic, e.g., morphine, and anendothelin antagonist for use in treating pain. Such a compositionprovides a safety factor for the patient because endothelinsignificantly regulates the autonomic nervous system (A. Gulati et al.,(1997); A. Kumar et al. (1997)), and a majority of the withdrawalreactions of morphine also are mediated through the autonomic nervoussystem. Therefore, endothelin is expected to modulate variouspharmacological actions of morphine and other opiate analgesics.

The present invention also is directed to a method of reducing orreversing tolerance to an opiate analgesic in an individual undergoingan opiate analgesic therapy by administering an endothelin antagonist tothe individual. In the absence of an administered dose of endothelinantagonist, the opiate analgesic dose would have to be increased overtime to achieve the same pain-reducing effect. Administration of anendothelin antagonist allows the opiate analgesic to be administered ata constant, or reduced, dose to achieve a desired pain treatment. Theconstant or reduced amount of opiate analgesic required to provide adesired pain-reducing effect thus reduces the severity of variousadverse side effects associated with opiate analgesic treatment, andreduces the possibility of opiate analgesic dependence.

The present invention also provides a method for improved paintreatment. In particular, the present invention is directed to methodsof using an opiate analgesic and an endothelin antagonist to preventand/or treat pain. More particularly, the present invention is directedto compositions containing morphine and an endothelin antagonist, and touse of an opiate analgesic and endothelin antagonist, administeredsimultaneously or sequentially, in methods of treating pain and reducingor reversing opiate analgesic tolerance and dependence.

An important aspect of the present invention, therefore, is to provide amethod and composition for preventing or treating pain, while reducingthe occurrence or severity of adverse side effects associated withopiate analgesic treatment.

Another aspect of the present invention is to reduce the problem ofdependence and addiction associated with present opiate analgesics usedto treat pain.

Still another aspect of the present invention is to provide a method ofreducing or reversing opiate analgesic tolerance in an individualundergoing an opiate analgesic therapy by administering atherapeutically effective amount of an endothelin antagonist to theindividual.

Yet another aspect of the present invention is to provide an article ofmanufacture for human pharmaceutical use, comprising (a) a packageinsert, (b) a container, and either (c1) a packaged compositioncomprising an opiate analgesic and an endothelin antagonist or (c2) apackaged composition comprising an opiate analgesic and a packagedcomposition comprising an endothelin antagonist.

These and other aspects of the present invention will become apparentfrom the following detailed description of the preferred embodiments ofthe invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an example of the groups of rats treated with avehicle, endothelin antagonist, morphine, and endothelin antagonist plusmorphine;

FIG. 2 contains plots for the effect of BQ123 pretreatment on analgesiainduced by morphine for four groups of treated rats;

FIGS. 3-5 contain plots for the effect of BQ123 pretreatment onanalgesia induced by morphine (2, 4, and 8 mg/kg, respectively), forfour groups of treated mice; and

FIGS. 6-8 contain plots showing a reduced morphine tolerance in miceafter treatment with the endothelin antagonists BQ123 or BMS182874.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is directed to the simultaneous or sequentialadministration of an opiate analgesic and an endothelin antagonist toprevent and/or treat pain. In particular, the administration of morphineand an endothelin antagonist to rats and mice show that the endothelinantagonist potentiates the analgesic effect of morphine, and, therefore,the dose of morphine can be reduced, while providing an analgesic effectequivalent to administering a higher dose of morpholine alone. Such acoadministration of active agents does not effect the catalepticproperties of morphine. The reduced dose of morphine also reducesadverse side effects associated with morphine administration, and cansignificantly reduce the addiction potential of morphine in susceptibleindividuals.

The present invention also is directed to the administration of anendothelin antagonist to an individual undergoing an opiate analgesictherapy to reduce or reverse opiate analgesic tolerance in theindividual. The administration of an endothelin antagonist allows thedose of opiate analgesic to remain constant, or to be reduced, whilemaintaining the desired pain-reducing effect. By reducing or reversingtolerance to an opiate analgesic, the occurrence of adverse side effectscan be reduced, and the possibility of opiate analgesic dependence isreduced.

The present invention, therefore, provides compositions and methods ofpotentiating the analgesic properties of an opiate analgesic, and ofreducing or reversing tolerance to opiate analgesics. The presentinvention also provides pharmaceutical compositions comprising an opiateanalgesic and an endothelin antagonist. Further provided are articles ofmanufacture comprising an opiate analgesic and an endothelin antagonist,packaged separately or together, and an insert having instructions forusing the active agents.

The methods described herein benefit from the use of an opiate analgesicand an endothelin antagonist in the treatment and management of pain.The analgesic and antagonist can be administered simultaneously orsequentially to achieve the desired effect of pain treatment orreduction or reversal of opiate analgesic tolerance.

For the purposes of the invention disclosed herein, the term “treatment”includes preventing, lowering, or eliminating pain. As such, the term“treatment” includes both medical therapeutic and/or prophylacticadministration, as appropriate.

The term “cataleptic” is defined herein as a trance-like conditionwherein a mammal's limbs remain in any position in which they areplaced, and there is an apparent loss of sensation and awareness.

The term “container” means any receptacle and closure therefore suitablefor storing, shipping, dispensing, and/or handling a pharmaceuticalproduct.

The term “insert” means information accompanying a product that providesa description of how to administer the product, along with the safetyand efficacy data required to allow the physician, pharmacist, andpatient to make an informed decision regarding use of the product. Thepackage insert generally is regarded as the “label” for a pharmaceuticalproduct.

The phrase “reducing or reversing opiate analgesic tolerance” is definedas the ability of a compound to reduce the dosage of an opiate analgesicadministered to an individual to maintain a level of pain controlpreviously achieved using a greater dosage of opiate analgesic.

Several neurotransmitter mechanisms have been proposed as playing a rolein the action of morphine and morphine tolerance and dependence.Evidence exists that a central endothelin (ET) mechanism is involved inthe actions of morphine. It has been found that ET antagonists,including BQ123, for example, can potentiate morphine-induced analgesiaand hyperthermia without affecting catalepsy. The present invention,therefore, provides a novel method of managing pain, reducing dependenceon opioids, and reducing tolerance to opioids.

Pharmacological agents can control most pain, but it is essential toselect the correct analgesic for the individual. Morphine is a majordrug for the treatment of moderate to severe pain (Foley, 1993).Morphine primarily is used to treat severe pain associated with trauma,myocardial infarction, and cancer. The use of morphine in the treatmentof chronic pain is limited because of inadequate analgesia, for example.Although, morphine is one of the most effective painkillers, effectivepain management requires that adequate analgesia be achieved withoutexcessive adverse side effects. Many patients treated with morphine arenot successfully treated because of excessive adverse side effectsand/or inadequate analgesia.

Management of excessive adverse side effects associated with morphineadministration remains a major clinical challenge. Numerous strategieshave been advanced to address this problem, such as (i) switchingopioids, (ii) switching routes of opioid administration, (iii) improvedopioid formulations, (iv) clonidine treatment, and (v) coadministratingopioids that act on different receptors.

A massive research effort directed to the development of opioidanalgesics, resulted in the discovery of numerous compounds having avarying affinity and efficacy at all the known opioid receptor subtypes.Although compounds of extremely high potency have been produced, theproblem of tolerance to, and dependence on, these agonists persists(Williams et al., 2001).

For example, the chronic administration of morphine results in thedevelopment of physical dependence, as evidenced by the appearance ofdistressing physical symptoms induced by abrupt termination of morphinetreatment. The signs and symptoms simulate a severe cold, and usuallyinclude nasal discharge, lacrimation, chills, goose pimples, muscularaches, enhanced motor reflexes, profound body water loss attributed tohyperthermia, hyperventilation, emesis, and diarrhea (Himmelsbach, 1943;Katz et al., 1986; Maldonado et al., 1996; Quock et al., 1968). It iswell known that various types of opioid receptors are involved in thedevelopment of the psychological and physical dependence on opioids.

The opioid receptors have been classified as μ, δ, and κ receptors,based on the relative affinity shown for experimental opioid receptorligands. μ-Opioid receptors have been reported to play a dominant rolein several pharmacological effects of morphine.

Role of μ-Opioid Receptors

An intracerebroventricular (i.c.v) injection of a selective andirreversible μ-opioid receptor antagonist, i.e., β-funaltrexamine(β-FNA), drastically antagonizes morphine induced antinociception(Portoghese et al., 1980; Takemori et al., 1981; Ward et al., 1982).β-FNA also inhibits the development of physical dependence on morphinein rats (Aceto et al., 1986; DeLander et al., 1984). Administration of aselective μ-opioid receptor antagonist, i.e.,D-Phe-Cys-Tyr-D-Trp-Arg-The-Pen-Thr-NH₂, into the lateral cerebralventricle 72 hours after subcutaneous implantation of two 75 mg pelletsof morphine in rats induces a severe withdrawal syndrome (Maldonado etal., 1992). The knockout mice with deleted μ-opioid receptors display noexpression of naloxone-precipitated withdrawal symptoms includingjumping and body weight loss (Matthes et al., 1996). It has beendemonstrated that μ-opioid receptors consist of μ₁ and μ₂ subtypes inthe central nervous system (CNS) (Goodman et al., 1985). Theirreversible μ₁-opioid receptor antagonist naloxonazine (Pasternak etal., 1980) is useful in investigating the function of μ₁-opioidreceptors. The CXBK recombinant inbred strain of mouse is deficient inμ₁-opioid receptors, and is much less sensitive than C57BL/6 progenitorstrain to the antinociceptive and locomotor effects of morphine(Moskowitz et al., 1985). In addition, the incidence ofnaloxone-precipitated jumping is much less in morphine-dependent C57BL/6mice (Suzuki et al., 1992a). The naloxone-induced body shakes alsooccurred at lower doses in C57BL/6 that in CXBK mice.

Role of δ-Opioid Receptors

Studies suggest that an interaction exists between μ- and δ-opioids. Ithas been found that at subantinociceptive doses, μ-opioid receptoragonists modulate antinociceptive responses to μ-opioid receptoragonists in mice (Jiang et al., 1990). Morphine acts mainly at theμ-receptor sites, but also can interact with δ-opioid receptors in vivoand in vitro (Narita et al., 1993). δ-Opioid receptor antagonists do noteffect morphine antinociceptive action. However, the selective blockadeof δ-opioid receptors by naltrindole (NTI) inhibits the development ofphysical dependence on morphine (Suzuki et al., 1997).

Role of κ-Opioid Receptors

Increasing evidence indicates that activation of κ-opioid receptoropposes a variety of μ-opioid receptor mediated actions throughout thebrain and spinal cord (Pan, 1998). Treatment with nor-binaltorphimine(nor-BNI), a selective κ-opioid receptor antagonist, when compared tonaloxone, did not precipitate weight loss or other withdrawal signs inmorphine-dependent mice (Cowan et al., 1988). Pretreatment with nor-BNIduring chronic morphine treatment displays aggravation of the weightloss precipitated by naloxone in morphine-dependent mice and rats(Suzuki et al., 1992b). These studies indicate that antagonism ofendogenous κ-opioidergic system apparently elicits a potentiating effecton some morphine-withdrawal signs, including weight loss. Stimulation ofendogenous κ-opioidergic system therefore should attenuate morphinewithdrawal symptoms. Dynorphin A has been reported to inhibit morphinewithdrawal symptoms induced by naloxone precipitation or morphinediscontinuation in morphine dependent animals (Suzuki et al., 1992a).However,3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide(i.e., U-50,488H), a selective κ-opioid receptor agonist, did notsuppress the development of physical dependence on morphine in rats(Fukagawa et al., 1989). This difference has been attributed to theaction of dynorphin A on all three subtypes of κ-opioid receptors, whileU-50,488H acts mainly on κ₁-opioid receptor subtype (Narita et al.,2001).

In summary, μ- and δ-opioid receptors show morphine-like withdrawalsymptoms, while κ-opioid agonists do not. An opposing interaction occursbetween μ/δ-opioid agonists and κ-opioid agonists.

Role of Nonopioid Receptors in Morphine Actions

Numerous studies, including molecular and genetic approaches, suggest asubstantial role of μ-opioid receptors in the development of morphinedependence and in numerous other actions of morphine. However, othersystems also are involved. A role for 5-HT and cholecystokinin systems,as well as N-methyl-D-aspartate (NMDA) receptors, in opioid placeconditioning has been proposed (Van Ree et al., 1999).

It has been widely reported that prototypical NMDA receptor antagonistsdizocilpine and ketamine, which have similar affinity for NR1/NR2A andNR1/NR2B receptors (Varney et al., 1996), suppress morphine-inducedplace preference (Avenet et al., 1997; Tzschentke et al., 1995).Evidence is accumulating that the NR2B subunit of NMDA receptors in thenucleus accumbens may be involved in the rewarding effect of morphine(Standaert et al., 1994; Watanabe et al., 1993). Neuroadaptive changesin specific brain regions that generate opioid dependence have beenidentified as noradrenergic transmission originating in the locusceruleus, and most likely play the primary causal role in the expressionof physical dependence on opioids. In contrast, a combination ofbehavioral and neurobiological studies point to the mesolimbicdopaminergic pathway projecting from the ventral tegmental area to thenucleus accumbens as a critical site for the initiation of psychologicaldependence on opioids.

Endothelin in the Central Nervous System

ET is an extremely potent endothelium derived vasoconstriction factor(Hickey et al., 1985) that was isolated, sequenced, and cloned(Yanagisawa et al., 1988). Endothelins are 21 amino acid, highly potentvasoconstrictive peptides with two disulfide bonds. Endothelins areproduced biologically by enzymatically cleaving preproendothelin toproendothelin, then to endothelin by endothelin-converting enzymes. ETexerts biological effects by binding to cell surface receptors which are7-transmembrane receptors coupled to G-proteins. There are two distincttypes of endothelin receptors, (a) the ET-1 selective ET_(A) receptorsprimarily found on vascular smooth muscle and responsible forvasoconstriction, and (b) nonselective ET_(B) receptors primarily foundin vascular endothelium and responsible for vasodilation.

The vasoconstrictive effects of ET-1 are mediated predominantly byG-protein coupled ET_(A) receptors (Reynolds et al., 1989). ET-1 also ismade in high concentrations by prostate, metastatic cancers, and CNS. ETin the CNS is produced by endothelial cells and nonendothelial cells,such as neurons, astrocytes, and glial cells (MacCumber et al., 1990).

The global distribution of ET and its binding sites in the brainsuggests that, in addition to being a vasoconstrictor, it may be actingas an important neuropeptide in the CNS (Gulati et al., 1992).Endothelin (ET) receptor antagonists, in particular selective ET_(A) orbalanced antagonists ET_(A)/ET_(B), represent a therapeutic area fordiseases such as congestive heart failure (CHF) and pulmonaryhypertension. BQ-123 and BMS-182874 are specific antagonists of ET_(A)receptors (Ihara et al., 1992; Stein et al., 1994). Endothelinantagonists have profound effects on the pulmonary vasculature and theright heart, whereas ACE inhibitors primarily affect the peripheralvessel and the left heart.

Several studies indicate that the central ET receptors are predominantlyof ET_(B) subtype (Matsumura et al., 1991). Rat cerebral astrocytes havebeen shown to express mainly ET_(B) type of receptors (Hama et al.,1992) and glial cells also were found to intensely express ET_(B)receptor mRNA (Pagotto et al., 1995). However, the centraladministration of a highly selective ET_(B) receptor agonist, IRL-1620,does not produce any effect on the cardiovascular system, and thesystemic and regional circulatory effects of centrally administered ET-1have been shown to be mediated through the ET_(A) receptors (Gulati etal., 1995; Rebello et al., 1995).

Intracerebroventricular administration of ET-1 produces a transient risefollowed by sustained fall in the mean arterial blood pressure (BP)(Gulati et al., 1996). The pressor effect was accompanied by an increasein renal sympathetic nerve activity and plasma levels of catecholaminesand arginine-vasopressin (Matsumura et al., 1991).

It also has been shown that the effects of central administration ofET-1 are mediated through activation of the sympathetic nervous systembecause these effects were attenuated by ganglion blockers (Kawano etal., 1989; Matsumura et al., 1991). Intracisternal administration ofET-1 elicited a transient increase in BP, renal sympathetic nerveactivity, and phrenic nerve activity. A subsequent fall in BP wasaccompanied by a decrease in renal sympathetic nerve activity andphrenic nerve activity (Kuwaki et al., 1994). The observation thatcentral ET-1 induced increase in pressor response was suppressed bypretreatment with phenoxybenzamine (Ouchi et al., 1989), furtherimplicates the active participation of sympathetic nervous system in theinitial pressor phase.

Interaction of Opioids and Endothelin

Both ET and opioids exist in the CNS and can play a role in regulationof cardiovascular and/or other functions. These two peptides can havesome interactions, especially through the sympathetic nervous systembecause both are located in sites involved in cardiovascular regulation,such as, for example, the hypothalamus, nucleus tractus solitarius, andlocus ceruleus. Very few studies exist indicating that ET and opioidsinteract and modulate the effects of one another.

For example, it has been reported that ET can induce pain, which can beblocked by morphine. ET-1 administered intraperitoneally intoCr1:CD-1(ICR)BR mice and CXBK mice produced abdominal irritation whichproduced a single occurrence of a wave of constriction and elongationpassing caudally along the abdominal wall accompanied by a mild twistingof the trunk followed by extension of the hind limbs. This ET-1 inducednociception could be blocked by morphine through μ₁ sensitive pathway(Raffa et al., 1994). In another study, ET-1 (200 to 800 μM) applied torat sciatic nerve produced reliable, robust, unilateral hindpawflinching lasting for 60 min. Pretreatment with morphine completelyblocked this effect in a naloxone sensitive manner. BQ123, an ET_(A)receptor antagonist, also blocked the ET-1 induced hind paw flinching(Davar et al., 1998). The role of ET_(A) receptor antagonist ABT-627 intactile allodynia has been investigated in streptozotocin-induceddiabetic rat model of neuropathic pain.

The systemic administration of ABT-627 produced a dose-dependentincrease (40 to 50%) in tactile allodynia thresholds. Theantinociceptive effect of ABT-627 was maintained following chronicadministration of the antagonist in drinking water for 7 days. Incomparison, morphine produced a significant (90%) increase in tactileallodynia thresholds. ET_(B) receptor antagonist did not affect thetactile allodynia threshold (Jarvis et al., 2000).

Responses to morphine can be associated with increased systemic andcerebrovascular levels of ET-1 and upregulation of ET-1 and ET_(A)receptor mRNA in the brainstem of newborn piglets (Modanlou et al.,1998). ET-1 administered intracerebroventricularly (i.c.v.) causedsignificant increases in mean arterial pressure and RSNA, and theseeffects were potentiated by naloxone pretreatment (Matsumura et al.,1994). The effect is centrally mediated because naloxone methobromide, analoxone derivative that does not cross the blood-brain barrier, did notalter the baroreflex sensitivity. It was concluded that ET-1 exerts apotent central pressor action mediated by enhanced sympathoadrenaloutflow, and naloxone potentiates these pressor and sympatheticresponses.

In accordance with an important feature of the present invention, it hasbeen hypothesized that actions of morphine and related opioids mediatedthrough the sympathetic pathway can be modulated by ET antagonists, andthat an interaction exists between opioids and ET. This approach isparticularly useful for the management of symptoms of morphinewithdrawal.

In accordance with another important feature of the present invention,an opiate analgesic is present in a composition, or is administered,with an endothelin antagonist in a weight ratio ofanalgesic-to-antagonist of about 0.01:1 to about 100:1, preferably about0.02:1 to about 50:1, and most preferably about 0.1:1 to about 10:1.This ratio depends upon the type and identity of opioid analgesic andendothelin antagonist being used. The ratio of analgesic-to-antagonistthat is administered is dependent upon the particular analgesic andantagonist used, and the origin and severity of the pain being treated.This ratio can be readily determined by a person skilled in the art toachieve the desired reduction in pain.

An opiate analgesic utilized in the present invention can be one or moreopium alkaloid or semisynthetic opiate analgesic. Specific opiateanalgesics include, but are not limited to, (a) opium; (b) opiumalkaloids, such as morphine, morphine sulfate, codeine, codeinephosphate, codeine sulfate, diacetylmorphine, morphine hydrochloride,morphine tartrate, and diacetylmorphine hydrochloride; and (c)semisynthetic opiate analgesics, such as dextromethorphan hydrobromide,hydrocodone bitartrate, hydromorphone, hydromorphone hydrochloride,levorphanol tartrate, oxymorphone hydrochloride, and oxycodonehydrochloride. Other opioids include, but are not limited to, fentanyl,meperidine, methodone, and propoxyphene.

An endothelin antagonist utilized in the present invention can be any ofthe endothelin receptor antagonists known in the art. Endothelin is apotent vasoconstrictor. Endothelin antagonists are used to treat acuteheart failure, congestive/chronic heart failure, pulmonary arterialhypertension, pulmonary edema, subarachnoid hemorrhage, chronicobstructive pulmonary disease, myocardial infarction, acute cerebralischemia, acute coronary syndromes, acute renal failure, post-operativetreatment in liver operations, and prostate cancer.

No adverse effects are expected when a healthy patient is administeredan opiate analgesic in combination with an endothelin antagonist.However, for patients suffering from conditions like congestive heartfailure and other diseases treatable by an endothelin antagonist,coadministration of an opioid analgesic and an endothelin antagonistshould be monitored carefully.

Preferred ET antagonists are antagonists selective for endothelin A(ET_(A)) receptors or are balanced ET_(A)/endothelin B (ET_(B))antagonists. Such ET antagonists are set forth in Appendices A and Bherein. However, endothelin B antagonists and miscellaneous endothelinantagonists, as set forth in Appendices C and D herein, also can be usedin a composition or method of the present invention. Additional usefulendothelin antagonists can be found in U.S. Patent ApplicationPublication No. US 2002/0082285 A1, incorporated herein by reference.

Specific examples of endothelin antagonists useful in the presentinvention include, but are not limited to, atrasentan, tezosentan,bosentan, sitaxsentan, enrasentan, BMS-207940 (Bristol-Myers Squibb),BMS-193884, BMS-182874, J-104132 (Banyu Pharmaceutical), VML 588/Ro61-1790 (Vanguard Medica), T-0115 (Tanabe Seiyaku), TAK-044 (Takeda),BQ-788, BQ123, YM-598, LU 135252, PD 145065, A-127722, ABT-627,A-192621, A-182086, TBC3711, BSF208075, S-0139, TBC2576, TBC3214,PD156707, PD180988, ABT-546, ABT-627, Z1611, RPR118031A, SB247083,SB217242, S-Lu302872, TPC10950, and SB209670.

BQ123 is a specific endothelin A antagonist, and is the sodium salt ofcyclo(-D-Trp-D-Asp-Pro-D-Val-Leu-). BQ-788 is a specific endothelin Bantagonist, and is the sodium salt ofN-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarbonyltriptophanyl-DNIe (see Proc. Natl. Acad. Sci. USA, 91, pp. 4892-4896(1994)).

In addition to a conventional endothelin antagonist, a compound thatinhibits the formation of endogenous endothelin also can be used as theendothelin antagonist in the present invention. Such compounds areuseful because they prevent endothelin formation, and, therefore,decrease the activity of endothelin receptors. One class of suchcompounds is the endothelin converting enzyme (ECE) inhibitors.

Useful ECE inhibitors include, but are not limited to, CGS34225 (i.e.,N-((1-((2(S)-(acetylthio)-1-oxopentyl)-amino)-1-cyclopentyl)-carbonyl-S-4-phenylphenyl-alaninemethyl ester) and phosphoramidon (i.e.,N-(a-rhamnopyranosyloxyhydroxyphosphinyl)-Leu-Trp).

The following tests were conducted to illustrate the potentiatingeffects of an endothelin antagonist on an opiate analgesic administeredto a mammal, including humans.

Male Sprague-Dawley rats weighing 225 to 250 g (Sasco King Animal Co.,Madison, Wis.) were housed in a room with controlled temperature (23±1°C.), humidity (50±10%), and light (6:00 a.m. to 6:00 p.m.) for at leastfour days prior to testing. Food and water were available to the ratscontinuously.

The rats were divided into four groups (FIG. 1): group 1 receivedvehicle (saline 5 μl, i.c.v. over 5 minutes) and vehicle (saline 100μl/kg s.c.); group 2 received vehicle (saline 100 μl/kg, s.c.) and BQ123(10 μg, i.c.v. in a volume of 5 μl over 5 minutes); group 3 receivedmorphine (8 mg/kg, s.c. in a volume of 100 μl/kg) and vehicle (saline100 μl/kg, s.c.); and group 4 received morphine (8 mg/kg, s.c. in avolume of 100 μl/kg) and BQ123 (10 μg, i.c.v. in a volume of 5 μl over 5minutes). Vehicle or BQ123 treatment was performed 30 minutes prior tomorphine administration.

Tests also were performed on mice. The mice were housed and fed similarto the rats as described above taking into consideration the sizedifferential between rats and mice. The mice were divided into groupsidentical to the rats, but administered different amounts of vehicle,opiate analgesic, and endothelin antagonist, as disclosed hereafter.

Measurement of analgesic effect: The analgesic response to morphine wasdetermined by the tail flick method. The tail flick latencies to thermalstimulation were determined before and 30, 60, 90, 120, 180, 210, 240,270, 300, and 360 minutes after the morphine injection. The basal tailflick latency was about 2 seconds. A cutoff time of 10 seconds was usedto prevent damage to the tail. The basal latency was subtracted fromthat induced by morphine. The analgesic response in each rat wasconverted into AUC_(0→360 min.) (area under the curve), and wasexpressed as mean±SEM. Eight to nine animals were used for each dose ofmorphine sulfate. The differences in analgesic response to differentdoses of morphine were compared by using student's t test. A value ofP<0.05 was considered significant.

Measurement of colonic temperature: The change in temperature inresponse to morphine was determined. The colonic temperature of each ratwas recorded before and various times after morphine injection for aperiod of 360 minutes using a telethermometer. The change in temperaturefrom the basal value was plotted with time and was converted toAUC_(0→300 min.) and was expressed as mean±SEM. Eight to nine rats wereused for each dose of morphine sulfate. Rats used to measure tail flicklatencies also were used to determine the colonic temperature. Thedifferences in temperature response between various groups were comparedby using student's t test. A value of P<0.05 was considered significant.

Measurement of catalepsy: Rats were tested for catalepsy by the bartest. An aluminum bar 5 mm in diameter was placed 4 cm above the floor,and the animal's forepaw was gently placed on the bar. The time requiredfor the animal to place at least one paw on the floor was measured witha maximum term of observation of 180 seconds. Behavioral evaluation ofcatalepsy was performed 45 minutes after the administration of morphineor its vehicle. Statistical tests were performed as described above.

Effect on body weight: Body weight was measured in all groups of rats ofFIG. 1. BQ123 pretreatment induced no change in body weight between thefour test groups. Body weight was measured before administering any drugand at the end of the experiment, i.e., seven hours after theadministration of morphine. The data clearly indicates that all groupswere very comparable in their response to change in body weight, andthat neither morphine nor BQ123 produced any acute effect on bodyweight.

Effect on cataleptic behavior: Morphine administration significantlyincreased catalepsy in rats. In contrast, BQ123 did not produce anycataleptic effect. Catalepsy is an overall indication of motor behaviorincluding locomotor activity of rats. Pretreatment with BQ123 did notproduce any change in morphine-induced catalepsy. In particular,morphine produced a significant increase in catalepsy compared tocontrol group 1, but this increase in catalepsy was not affected byBQ123 pretreatment. Therefore, the effect of morphine on catalepticbehavior was not affected by administration of the endothelin antagonistBQ123. These findings indicate that BQ123 did not affect apharmacological action produced in rats by morphine.

Effect on body temperature: The control treated rats (group 1 of FIG. 1)did not show any effect on body temperature. BQ123 treatment also didnot produce any significant effect on body temperature. Morphinetreatment produced significant hyperthermia in rats. Hyperthermia lastedfor about four hours after the administration of morphine. Thehyperthermic effect of morphine was significantly potentiated by BQ123.The hyperthermic effect of morphine was not only significantly greaterin BQ123 pretreated rats, but lasted for more than six hours. Inparticular, it was demonstrated that morphine produced a significantincrease in body temperature compared to control group 1. Pretreatmentwith BQ123 significantly potentiated the effect of morphine-inducedhypothermia compared to vehicle and morphine-treated rats. This is asignificant observation because although morphine-induced catalepsy isnot affected by endothelin antagonist BQ123, the hyperthermic responseto morphine is potentiated by BQ123.

Effect on analgesia: The control group of rats exhibited tail flicklatencies of about 2 seconds. BQ123 treatment did not produce anysignificant effect on tail flick latency. Morphine (8 mg/kg, s.c.)produced significant analgesia in rats, and the tail flick latenciesreached more than 10 seconds (FIG. 2). A significant increase in tailflick latencies was observed until three hours after the administrationof morphine. The analgesic effect of morphine was significantlypotentiated by BQ123. The analgesic effect of morphine not only wassignificantly greater in BQ123 pretreated rats, but lasted for more thansix hours.

The effect of BQ123 treatment (3 μg, i.c.v.) on morphine analgesia alsowas determined in mice (FIGS. 3-5). Morphine (2, 4, and 8 mg/kg, s.c.)produced a significant increase in mouse tail flick latency that lastedfor 1.5 hours. BQ123 significantly potentiated morphine analgesia, whichlasted for more than 4 hours. FIG. 3 especially shows that tail flicklatency is increased by administration of BQ123, thereby showing anendothelin antagonist potentiating effect on morphine at a low dosageadministration of the opiate analgesic.

FIGS. 6-8 illustrate the ability of an endothelin antagonist to induceopiate analgesic tolerance in mice and rats rendered tolerant anddependent on morphine. The test method used to generate the data setforth in FIGS. 6-8 is disclosed in H. N. Bhargava et al., J. Pharmacol.Exp. Ther., 252(3), pp. 901-907 (1990). The method disclosed therein wasmodified slightly for mice because the smaller mice could not survivethe morphine dose administered to the rats. Tolerance to morphine isdemonstrated in FIGS. 6-8 for the endothelin antagonists BQ123 andBMS182874.

The effect of BQ123 (3 μg, i.c.v.) on naloxone-precipitated morphinewithdrawal also was determined in mice. Naloxone (1 mg/kg, i.p.)administration to morphine tolerant mice (1 morphine 75 mg pellet for 3days) resulted in expression of withdrawal symptoms. BQ123 did notaffect hypothermia, loss of body weight, jumping behavior, falls,diarrhea, fecal boli, urination, ptosis, writhing, and rearing behaviorduring withdrawal. Tests also were performed to determine tolerance toanalgesic effect in morphine tolerant dependent rats (6 morphine pelletsin 7-day period). BQ123-treated (10 μg, i.c.v., twice a day for 7 days)rats did not become tolerant to morphine.

These studies demonstrate that an endothelin antagonist, like BQ123,potentiates the analgesic effect of morphine and prevents thedevelopment of tolerance to morphine analgesia, without affectingnaloxone-precipitated morphine withdrawal. The combined use of BQ123 orother ET antagonist and an opiate provides a novel approach to improvinganalgesia and eliminating morphine tolerance. These findings provide anovel combination of active agents to manage various types of pain.

In summary, rat and mice studies showed that endothelin antagonistadministration in combination with an opiate analgesic potentiatedanalgesia and hypothermia, but did not affect catalepsy or body weight.A mouse study administering BQ123 and morphine (2, 4, or 8 mg/kg) alsoshowed that analgesia was potentiated, but hypothermia and body weightwere not affected.

Another study directed to naloxone (1 mg/kg) initiated withdrawalsymptoms in mice in conjunction with a combination morphine and BQ123treatment showed no effect on temperature, body weight, urination,diarrhea, jumping behavior, number of falls, ptosis, and grooming.

Overall, test results show that an endothelin antagonist significantlypotentiates morphine analgesia in mice and rats, prevents thedevelopment of tolerance to analgesic actions of opiate analgesics, likemorphine, and potentiates morphine-induced hyperthermia in rats, butdoes not affect morphine-induced hypothermia in mice, does not affectmorphine-induced catalepsy in rats, and does not affect naloxoneprecipitated morphine withdrawal. Therefore, an endothelin antagonistpotentiates morphine analgesia, but does not potentiate morphinewithdrawal symptoms and prevents or reverses the development oftolerance to analgesic opiates.

The test results clearly demonstrate that endothelin antagonists, likeBQ123, potentiate morphine-induced analgesia and hyperthermia withoutaffecting morphine-induced cataleptic behavior. This is an importantclinical finding because endothelin antagonists have minimalcardiovascular effects in normal healthy individuals and because ETantagonists, like tezosentan, bosentan, darnsentan, and atrasentan, arenearing regulatory approval. Endothelin antagonists combined withmorphine, therefore, can be used to potentiate the analgesic action ofmorphine without affecting some of the other pharmacological actions ofmorphine.

It has been demonstrated that ET significantly regulates the centralautonomic nervous system (Gulati et al., 1997; Kumar et al., 1997), andmost of the withdrawal reactions of morphine also are mediated throughthe central autonomic nervous system. Central ET modulatespharmacological actions of morphine. Using an ET antagonist togetherwith morphine increases the analgesic and hyperthermic action ofmorphine, but does not affect the cataleptic action of morphine. On thebasis of results obtained, an ET antagonist can reduce the dose ofmorphine and still produce same degree of analgesic action of morphineas produced by a higher dose of morphine used alone. Lowering the doseof morphine can significantly reduce the addiction potential of morphinein patients.

These findings show that when combined with an endothelin antagonist,morphine and other opiate analgesics produce significant analgesia witha much lower dose of analgesic, and, therefore, the addiction potentialof the opiate analgesic is reduced. These observations also indicatethat the duration of analgesic response of morphine can be significantlyincreased by administration of an endothelin antagonist.

The data shows that some morphine-induced pharmacological responses,like change in temperature and analgesia, can be separately potentiatedwhile other responses, like catalepsy, are not affected by endothelinantagonist administration.

The above tests and data show that a combination of an opiate analgesicand an endothelin antagonist can be administered to mammals in methodsof treating pain. The opiate analgesic and endothelin antagonist can beformulated in suitable excipients for oral administration, or forparenteral administration. Such excipients are well known in the art.The active agents typically are present in such a composition in anamount of about 0.1% to about 75% by weight, either alone or incombination.

Pharmaceutical compositions containing the active agents, i.e., opiateanalgesic and endothelin antagonist, of the present invention aresuitable for administration to humans or other mammals. Typically, thepharmaceutical compositions are sterile, and contain no toxic,carcinogenic, or mutagenic compounds that would cause an adversereaction when administered.

The method of the invention can be accomplished using the active agentsas described above, or as a physiologically acceptable salt or solvatethereof. The active agents, salts, or solvates can be administered asthe neat compounds, or as a pharmaceutical composition containing eitheror both entities.

The active agents can be administered by any suitable route, for exampleby oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternalthrough lumbar puncture, transurethral, nasal, percutaneous, i.e.,transdermal, or parenteral (including intravenous, intramuscular,subcutaneous, and intracoronary) administration. Parenteraladministration can be accomplished using a needle and syringe, or usinga high pressure technique, like POWDERJECT™. Administration of theactive agents can be performed before, during, or after the onset ofpain.

The pharmaceutical compositions include those wherein the activeingredients are administered in an effective amount to achieve theirintended purpose. More specifically, a “therapeutically effectiveamount” means an amount effective to prevent development of, toeliminate, or to alleviate pain. Determination of a therapeuticallyeffective amount is well within the capability of those skilled in theart, especially in light of the detailed disclosure provided herein.

A “therapeutically effective dose” refers to the amount of the activeagents that results in achieving the desired effect. Toxicity andtherapeutic efficacy of such active agents can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., determining the LD₅₀ (the dose lethal to 50% of the population)and the ED₅₀ (the dose therapeutically effective in 50% of thepopulation). The dose ratio between toxic and therapeutic effects is thetherapeutic index, which is expressed as the ratio between LD₅₀ andED₅₀. A high therapeutic index is preferred. The data obtained from suchdata can be used in formulating a range of dosage for use in humans. Thedosage of the active agents preferably lies within a range ofcirculating concentrations that include the ED₅₀ with little or notoxicity. The dosage can vary within this range depending upon thedosage form employed, and the route of administration utilized.

The exact formulation, route of administration, and dosage is determinedby an individual physician in view of the patient's condition. Dosageamounts and intervals can be adjusted individually to provide levels ofactive agents that are sufficient to maintain therapeutic orprophylactic effects.

The amount of active agents administered is dependent on the subjectbeing treated, on the subject's weight, the severity of the affliction,the manner of administration, and the judgment of the prescribingphysician.

Specifically, for administration to a human in the curative orprophylactic treatment of pain, oral dosages of an opiate analgesic andendothelin antagonist, individually generally are about 10 to about 200mg daily for an average adult patient (70 kg), typically divided intotwo to three doses per day. Thus, for a typical adult patient,individual tablets or capsules contain about 0.1 to about 200 mg opioidanalgesic and about 0.1 to about 50 mg endothelin antagonist, in asuitable pharmaceutically acceptable vehicle or carrier, foradministration in single or multiple doses, once or several times perday. Dosages for intravenous, buccal, or sublingual administrationtypically are about 0.1 to about 10 mg/kg per single dose as required.In practice, the physician determines the actual dosing regimen that ismost suitable for an individual patient, and the dosage varies with theage, weight, and response of the particular patient. The above dosagesare exemplary of the average case, but there can be individual instancesin which higher or lower dosages are merited, and such are within thescope of this invention.

The active agents of the present invention can be administered alone, orin admixture with a pharmaceutical carrier selected with regard to theintended route of administration and standard pharmaceutical practice.Pharmaceutical compositions for use in accordance with the presentinvention thus can be formulated in a conventional manner using one ormore physiologically acceptable carriers comprising excipients andauxiliaries that facilitate processing of the active agents intopreparations that can be used pharmaceutically.

These pharmaceutical compositions can be manufactured in a conventionalmanner, e.g., by conventional mixing, dissolving, granulating,dragee-making, emulsifying, encapsulating, entrapping, or lyophilizingprocesses. Proper formulation is dependent upon the route ofadministration chosen. When a therapeutically effective amount of theactive agents are administered orally, the composition typically is inthe form of a tablet, capsule, powder, solution, or elixir. Whenadministered in tablet form, the composition can additionally contain asolid carrier, such as a gelatin or an adjuvant. The tablet, capsule,and powder contain about 5% to about 95% of an active agent of thepresent invention, and preferably from about 25% to about 90% of anactive agent of the present invention. When administered in liquid form,a liquid carrier, such as water, petroleum, or oils of animal or plantorigin, can be added. The liquid form of the composition can furthercontain physiological saline solution, dextrose or other saccharidesolutions, or glycols. When administered in liquid form, the compositioncontains about 0.5% to about 90% by weight of active agents, andpreferably about 1% to about 50% of an active agents.

When a therapeutically effective amount of the active agents isadministered by intravenous, cutaneous, or subcutaneous injection, thecomposition is in the form of a pyrogen-free, parenterally acceptableaqueous solution. The preparation of such parenterally acceptablesolutions, having due regard to pH, isotonicity, stability, and thelike, is within the skill in the art. A preferred composition forintravenous, cutaneous, or subcutaneous injection typically contains, inaddition to a compound of the present invention, an isotonic vehicle.

Suitable active agents can be readily combined with pharmaceuticallyacceptable carriers well-known in the art. Such carriers enable theactive agents to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained by adding the active agents with a solidexcipient, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients include, forexample, fillers and cellulose preparations. If desired, disintegratingagents can be added.

The active agents can be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection can be presented in unit dosage form, e.g., in ampules orin multidose containers, with an added preservative. The compositionscan take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and can contain formulatory agents, such assuspending, stabilizing, and/or dispersing agents.

Pharmaceutical compositions for parenteral administration includeaqueous solutions of the active agent in water-soluble form.Additionally, suspensions of the active agents can be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils or synthetic fatty acid esters. Aqueousinjection suspensions can contain substances which increase theviscosity of the suspension. Optionally, the suspension also can containsuitable stabilizers or agents that increase the solubility of thecompounds and allow for the preparation of highly concentratedsolutions. Alternatively, a present composition can be in powder formfor constitution with a suitable vehicle, e.g., sterile pyrogen-freewater, before use.

The active agents also can be formulated in rectal compositions, such assuppositories or retention enemas, e.g., containing conventionalsuppository bases. In addition to the formulations described previously,the active agents also can be formulated as a depot preparation. Suchlong-acting formulations can be administered by implantation (forexample, subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, the active agents can be formulated withsuitable polymeric or hydrophobic materials (for example, as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

In particular, the active agents can be administered orally, buccally,or sublingually in the form of tablets containing excipients, such asstarch or lactose, or in capsules or ovules, either alone or inadmixture with excipients, or in the form of elixirs or suspensionscontaining flavoring or coloring agents. Such liquid preparations can beprepared with pharmaceutically acceptable additives, such as suspendingagents. An active agent also can be injected parenterally, for example,intravenously, intramuscularly, subcutaneously, intrathecally,intracisternally, or intracoronarily. For parenteral administration, theactive agent is best used in the form of a sterile aqueous solutionwhich can contain other substances, for example, salts, ormonosaccharides, such as mannitol or glucose, to make the solutionisotonic with blood.

For veterinary use, the active agents are administered as a suitablyacceptable formulation in accordance with normal veterinary practice.The veterinarian can readily determine the dosing regimen and route ofadministration that is most appropriate for a particular animal.

As stated above, morphine is one of the most potent analgesics, and iswidely used for pain management in several disease conditions, includingcancer. A major problem in the use of morphine, and other opiateanalgesics, is their potential to produce sedation tolerance/dependent,and respiratory depressions, and to cause addiction.

It has been discovered that using an endohelin antagonist in combinationwith an opiate analgesic potentiates the analgesic and hyperthemicaction of the analgesic, but does not increase the sedative orcataleptic action of the analgesic. The combined opiateanalgesic-endothelin antagonist treatment can be used, for example, inoffice surgeries, oral surgeries, and post-surgical pain management.

It also has been discovered that by using an endothelin antagonisttogether with an opiate analgesic, the dose of morphine can be reduced,and still provide the same analgesic action as a larger dose of morphineused alone. By using less morphine, the addiction potential of an opiateanalgesic in patients can be reduced significantly. The administrationof an endothelin antagonist to an individual undergoing opiate analgesictreatment, therefore, reduces or eliminates tolerance to opiateanalgesics.

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Modifications and variations of the invention as hereinbefore set forthcan be made without departing from the spirit and scope thereof, and,therefore, only such limitations should be imposed as are indicated bythe appended claims.

What is claimed is:
 1. A method of reducing or reversing tolerance to anopiate analgesic in an individual undergoing opiate analgesic therapycomprising administration of a therapeutically effective amount of aspecific endothelin-A antagonist, wherein the specific endothelin-Aantagonist is BQ123.
 2. The method of claim 1 wherein the opiateanalgesic and endothelin antagonist are administered simultaneously. 3.The method of claim 2 wherein the opiate analgesic and endothelinantagonist are administered from a single composition.
 4. The method ofclaim 2 wherein the opiate analgesic and endothelin antagonist areadministered from separate compositions.
 5. The method of claim 1wherein the opiate analgesic and endothelin antagonist are administeredsequentially.
 6. The method of claim 5 wherein the opiate analgesic isadministered prior to the endothelin antagonist.
 7. The method of claim5 wherein the endothelin antagonist is administered prior to the opiateanalgesic.
 8. The method of claim 1 wherein the opiate analgesic isselected from the group consisting of an opium alkaloid, a semisyntheticopiate analgesic, and a mixture thereof.
 9. The method of claim 1wherein the individual is a human.